Spirocyclohexanes and methods of preparation thereof



Patented Jan. 5, 1954 "SPIRO CYGLOHEXANES ANDiMETHODS OF PREPARATIONTHEREOF Gilbert Forrest Woods, J r., and Louis H.

Sehwartzman, Silver Spring, .Md.

-"No Drawing. Application November 24,1951, Serial No. 258,092

6' Claims. 1 This invention relates to compounds of the spirocyclohexanetype and methods of preparation thereof.

- More particularly, the invention relates-to'the synthesis of compoundsof the spirocyclohexane type, particularly those having analgesicproperties such as possessed by morphine-and other opiates derived fromnatural sources.

Considerable effort has been directed in the past toward the synthesisof 'suitableanalgesics as substitutes for morphineand the like,particularly in view of the fact thatthe principal source of supply ofmorphine andrelatedzcompounds is dependent upon natural sources, most ofwhich are presently located in the Orient. In an effort to producechemically synthesized analgesics domestically on an economicallypracticable basis, and toprovide a source of analgesics independent ofnatural supplies of raw materials, many attempts have been made tosynthesize various analgesics as substitutes for morphine and the like,some of the more recently developed compounds 'Jbeing Demerol Methadonetc.

Among other things, it has, beenfound that many synthetic compoundsproduced heretofore, although having some of the analgesic properties ofmorphine and the like, are not satisfactory from the standpoint ofmanufacturing costs, and even in some casesare unsuitable for use byhuman beings because of their high toxicity or side-eliects and otherundesirable properties.

It is found that compounds of the present invention are not onlyrelatively simple and inexpensive to manufacture from readil availableraw materials but; inaddition, have satisfactory analgesic propertiesand are of sufficiently low toxicity topermit safe use by human beings.

In its more specific aspects the present invention pertains to thesynthesis of analgesic compositions of the spirocyclohexane type byemploying cyclohexanone as a starting material and producing therefrom alarge number of new, novel and' useiul analgesic compounds containing aquaternary carbon atom in the molecule and, in addition, either aprimary, secondary,,or tertiary'amine group.

The invention also provides new and novel methods of preparing thecompounds described herein, such methods being particularly advantageousin view of the simplicity of the procedures, economic practicability andcomparatively high yields of the intermediates and the end productswithout the use of complicated or expensive starting materials,apparatus, or processes.

".The intermediates required for synthesis of the compounds of thepresent invention may be prepared, for example, in the manner describedin copending application Serial No. 150,806, filed March 20, 1950, nowPatent No. 2,586,486, by using cyclohexanone as a starting material,treating it with a mixture of calcium carbide and potassium hydroxide toyield an acetylenic glycol such as 1,1'-ethynylene-bis-cyclohexanolaccording to the reaction:

vO II This glycol (II) is then dehydrated to the dieneyne (III) by, forinstance, heating the above glycol under reflux conditions with dilutesuliuric acid as follows:

/OH OH CEQAO H250 @rCECO The compound thus obtained is then cyclized andhydrated, for example, by refluxing with formic acid, thus producing asintermediates, cyclic ketones such as spiro[cyclohexane-1,1'-A9-tetrahydroindanone-3] (IV) and its isomer spiroEcyclohexane 1,1 A8tetrahydroindanone-B'] (V) in accordance with the following reaction:

CEO

ll (III) and/ or To produce the analgesic compounds of the presentinvention, the cyclic ketones (IV) and/or (V) are converted to theketone (VI) and subsequently to its oxime (VII) according to thereaction:

y Catalyst l W (IV) and/or (VI) (VII) and thereafter the oxime (VII) ishydrogenated in the presence of a catalyst to produce an analgesicspiroindane in accordance with the reaction:

catalyst (PtOz. Hz) o W o It H NH: H (VIII) By further treatment of thespiroindane (VIII) according to the following reaction, compound (IX) isobtained, this compound being an important intermediate for thepreparation of the compounds of the present invention:

CH1 (VIII) (IX) The compounds (VIII) and (IX) and methods of preparationthereof are disclosed and claimed in copending application Serial No.150,808, filed March 20, 1950, now Patent No. 2,585,969.

The compounds of the present invention, as distinguished from thosedisclosed and claimed in said copending applications Serial Nos.150,808, now Patent No. 2,585,969, and 150,810, now abandoned, eachfiled March 20, 1950, in that the present compounds are substitutedspirocyclohexanes of the type:

It is an object of the presentinvention, therefore, to provide aseriesof substituted spiroindanes. More particularly "it is an object toprovide substituted"spiroindanes' having analgesic:properties. 'Itisafurther'fobjeot of the present invention to provide "a "series ofsubstituted 'spiroindanes having a' quaternary carfloon atom and,inaddition aprimary, secondary or tertiary amine group in the molecule.It is a still further object ofthe present-invention to provide methodsof preparation of the compounds of the invention.

For purposes of illustration, but without intending to limit the scopeof the patent thereto, representative methods and compounds of thepresent invention aresdescribed in the following examples:

EXAMPLE I A compound of the type:

ED. H l

cooled to 0 C. and with vigorousstirring;-9.4-ml. of concentratedsulfuricacid is added dropwise.

The mixture is cooled to -3 C., and a solution crave gramsof potassiumnitrate in- 8.4 m1; of

concentrated sulfuric acidis addeddropwi'se with vigorous stirring overa period of ZG-minutes. "I-he temperature-at theend of the additionwastC1,

the resulting two phase system is stirredat this temperature for anhour-and the carbon tetrachloride layer decanted away. Upon pouring thebrown oil with stirring onto ice, a. precipitate is formed which isdifficult to filter. Therefore,

it is neutralized with ammonium hydroxide-and extracted with ether.filtered.

This extract is dried and Absolute alcohol (10 ml.) saturated withhydrogen chloride gas is added to the filtereddry ether extract to give7 grams-of OzN- /O H lTTCH3 .CHz

EXAlWIPLE 1(a) A compound having the formula:

after recrystallization from methanol-water mixtures and sublimation atreduced pressure. melted at 9799 C. The amine hydrochloride formed inthe usual manner and recrystallized from alcohol- An extremely effectiveanalgesic compound of the type:

wherein X is the amino group and R1 and R2 are lower alkyl groups may beprepared as follows:

A mixture of 3.7 grams of spiroEcyclohexane- 1,1 3dimethylamino-xnitroindanel hydrochloride dissolved in 50 ml. of 95%alcohol is stirred and refluxed. To this refluxing mixture, 17.7 gramsof SnC12-2H2O dissolved in 16.9 ml. concentrated hydrochloric acid and21 ml. 95% alcohol is added over a period of twenty minutes. Afterboiling for an additional thirty minutes, the alcohol is removed underreduced pressure and the resulting complex is decomposed with a largeexcess of aqueous potassium hydroxide. The solution is then extractedwith ether, the ether is dried over magnesium sulfate and upondistillation of the dried ether extract under reduced pressure 2.9 gramsof solid di-amine is obtained as a residue. The di-amine,spiro[cyc1ohexane 1,1-x-amino-3'-dimethylaminoindane], is sublimed at120 C. and 1 mm. This affords a white crystalline sample melting atl14-l16 C. The compound has the formula:

This compound possesses the analgesic effects on white mice described inthe following chart:

M. E. D.:

5 mg./kg. body weight. L. D50;

'75 mg./ kg. body weight.

EXAMPLE 11((1) A compound having the formula:

EXAMIPLE III A compound having the formula:

NEC-

may be prepared as follows:

SpiroEcyclohexane 1,1-x-cyano-3'-dimethylaminoindane]. A solution of 10g. (.041 mole) of the diazonium salt ofspiro[cyclohexane-1,1xamino-3dimethylaminoindane] cooled to 0 wascarefully neutralized with sodium bicarbonate. This solution was addeddropwise to a, freshly prepared mixture of 0.041 mole of cuprous cyanidecovered with 200 ml. of toluene which was cooled to 0 and vigorouslystirred. After the addition the mixture was stirred for one-half hour at0, four hours at room temperature, and finally heated to 50 for threehours. The cooled mixture was made alkaline with sodium hydroxide andextracted with ether. The organic layer was extracted with dilutehydrochloric acid. The aqueous layer was neutralized, extracted withether, dried, and the dried ether layer was concentrated under reducedpressure to yield 8 g. of a dark brown oil. The hydrochloride, made bypassing hydrogen chloride gas into an ether solution of the amine, wasdissolved in alcohol and treated with a few grams of stannous chlorideand hydrochloric acid and finally charcoal to effect an efficientdecolorization. The slightly yellowish hydrochloride was recrystallizedfrom alcohol and melted at 257-260.

The free cyanoamine, spiro[cyclohexane-l,1-x-cyano-3'-dimethylaminoindane], was regenerated with dilute ammoniumhydroxide and after recrystallization from petroleum-ether (20-40) andsublimation at reduced pressure melted at 81-82% EXAMPLE IV A compoundof the type:

wherein X is the hydroxyl group and R1 and R2 are methyl groups may beprepared as follows:

3.5 grams of spiro[cyclohexane-1,1-x-amino- 3-dimethylaminoindane]prepared in accordance with the procedure of Example 11, is dissolved ina solution of 2.2 m1. concentrated sulfuric acid in 75 ml. water, iscooled to 0 C., with an icesalt bath and is stirred vigorously. Then 1.1grams of sodium nitrite in 10 m1. of water cooled to 0 C. is addeddropwise over a period of ten minutes. After destroying the excessnitrous acid with urea, 5 ml. of concentrated sulfuric acid in 5 ml. ofwater is added and the mixture is heated on the steam bath to 97 C. forone hour. Clarification of the red aqueous solution with charcoal andsubsequent cooling yields 1.75 grams of the white crystalline phenolicamine sulfate. The crystals are recrystallized twice from about 400 ml.of boiling water, to give colorless material QHa EXAMPLE 2V A.. mpo.undof-the typ wherein .X.liS; the hydroxyl r p; 1 d z:

are hydrogen may be; prepared as follows;

A solution; ofhspiroicyclohexane-1,1f -ind anone, 3'] (18.2 g.)dissolved in 100-m l., of; COIICGH. trated sulfuric acid is cooled to C.To this is added dropwiselotgr of potassium nitrate dissolved in 30 ml.of concentrated sulfuric acid with stirring over a period of l hours,after which the stirring-was continued'foran additional hour at 0 C. Thereaction mixture is then poured withyigorous stirring onto ice. Theyellow solid precipitate. of nitroketone is filtered and the solidfractionally crystallized from acetone and 18 g. of material melting at193-195 is obtained. Furthercrystallization from benzene yieldshexagonal, slightly yellow crystals of spirofcyclohexane 1,1 xnitroindanone 3'] melting at 195-1955".

A solution of spiro[cyclohexane-l,1'-x-nitroindanone-3l (14.1 g.)1121790. mlrofg 95;%-ia1 Q V is stired and refluxed; to, this'is: addedin; dropwise; mannera' a. solutien; of; 411 s g SIIQIZZHZQ' in; &0 ml.ofzconcentrated;hydrochloric acid; and -20;

ml. of 95%; alooholzi. After: ref uxin feran: additionalgthirty ririutes, theirselyent is; removed under reducedpressure 1 and thecomplexdecenc posed With. a lar e;excess:.ofrconcen ra edznota slum; hydroxidesolu icn; The alkal..ine.1 el ticnrr is extracted with ether, the etherextract dried and the dry extract is. distilled under reduced pressureto leave as a residue, spircEcyclohexane- 1,1 x-aminoindanone-3 Aftercrystallization of the residue from benzene-petroleum ether mixtures andsubsequent sublimation at 120 C. at 0.5 mm... 11g. of the aminoketone isobtained which melts at 125-12 6 C.

SpiroEcyclohexane 1,1 x-aminoindanone- 3'] (10.5 g.) in a solution of 11ml: of'concentrated sulfuric acid-and 80 ml. of water is diazotized at3-5" C. with 3.5 g. NaNOz in 20 ml. of water over a period of thirtyminutes. After decomposition of the excessnitrous acid with urea, thesolution is filtered and, after addition of ml. of concentratedsulfuric'acid'in; ml. of water is heatedfor 1,%* 11011I'5 5 on aasteamcone. After; cessation; of the nitrogen: evolut qni the,

10.12v phenolic ;-ketone appears as an orange oil, which solidifies-Orrcooling. The solid phenolic ketone isidissolved. in :eth er andextracted with aqueous potassium hydroxide,- and the alkaline extractneutralized; carefully with hydrochloric acid.

The resulting yellowprecipitate, is recrystallized from alcohol-waterand then sublimed at 160 C. and 0.03 mm. to yield17.6. g. ofspiro[cyc1ohexane-1,1'-x-hydroxyindanone-3 which melts at 159-160 C.

Spiro[cyclohexane 1,1} x hydroxyindanone-3'] (5 g.) is-added to amixture of hydroxylamine hydrochloride (5 g.), pyridine (14 ml.), andanhydrous al cohol-.-(30 ml.), and the solution is refluxed for 2 hours.Removal of the solvent underreduced pressure, and recrystallization ofthe crystalline mass from alcoholwater mixtures affords the oxime ofspiro[cy-.

clohexanfirl,lxehymoxyindanonee3'1 which melts,.at.182-184 C.

The oxime of spiro[cyclohexane-1,1-x-hydroxyindanoner3'] (13 g.)ishydrogenated at room temperature and 20 pounds of hydrogen with, 0.5g.of platinum oxide as av catalyst in 100 ml, ofuglacialacetic. acid.After cessation of hydrogen absorption, the catalyst is removed byfiltration. The filtrateiscooled and neutralized with ammonium hydroxideto yield a white crys talline precipitate: After:- crystallization fromc alcohol-water mixtures, 10 g. of spiroEcyclohexane 1,1 3' amin9;:-

-.hydroxyine dane] is obtained which melts at 227-228 C This compoundhas-the formula:

by anzalternative method; as follows:

spirolcyclohexane 1,1. -.3fi aminoindane] can: be initrated; as-- the- Nl-acetyl derivative in a. solution of carbon -tetrachloridewith ethertum-- ingnitric acid or a-mixture of potassium nitrate and sulfuricacid. The-resulting nitro-N-acetyl-V amine canbe isolatedginthe usualmanner andv subsequently reduced with a variety of reducing. agents, forexample, QnGIz2H2O+HCL to the corresponding diamine; spiro[cyclohexane-l,1 3'-acetylamino-x-aminoindanel, The, diamine in turn canbe diazotized in the usual manner and then heated torefiux for about 24hours with a 50% solution of H280; and then cooled and neutralized withNH4OH to yield spiro[cyclohexane-1,1-3'amino-x-hydroxyindane].

The compound of; Example IV may be obtained by another method, asfollows:

1 lization on the compound; from" acetone aiiords;

11 a white crystalline compound which melts at 159-179 and gives nodepression in a mixed melting point determination with spiroEcyclohexane1,1 3' dimethylamino x hydroxyindane] prepared as indicated earlier.

EXAMPLE VII A compound of the type:

wherein X is a halogen and R1 and R2 are methyl groups may be preparedas follows:

Spiro[cyclohexane 1,1 x amino 3 dimethylaminoindane] can be diazotizedas indicated in Example III. The diazonium salt solution is then treatedwith potassium iodide and the mixture stirred at room temperature untilthe evolution of nitrogen ceases. Isolation in the usual manner affordsspiro[cyclohexane-l,l-3- dimethylamino-x-iodoindane] EXAMPLE VIII Acompound of the type:

EXAMPLE IX A compound of the type:

where X is acetate and R1 and R2 are methyl groups may be prepared asfollows: Spiro [cyclohexane 1,1 3 dimethylaminox-hydroxyindane] isdissolved in 4 molar equivalents of acetic anhydride and then acatalytic amount of pyridine added. After several days at roomtemperature, the solvent is removed under reduced pressure to yieldspiro [cyclohexa 1,1'-x-acetoxy-3'-dimethylaminoindanel,

The dried ether extract is then con- 12 EXAMPLE 2:

A compound having the formula:

1 Oils-3' J may be prepared as follows:

Spiro [cyclohexane 1,1 3' dimethylamino- X-(l-hydroxyethyl) indane]. Toan efliciently stirred solution of 20 ml. of 1.3 molar lithium aluminumhydride in ether was added dropwise 3 g. of spiro cyclohexane 1,1 xacetyl-3'-dimethylaminoindane) in ml. of anhydrous ether. After theaddition, the mixture was stirred for an additional half hour and thensufficient water was added in the cold to just decompose the excessreagent and the complex. The ether layer Was washed with water, driedover anhydrous magnesium sulfate, and after removal of the drying agent,concentrated to give 3 g. of the hydroxy compound. Since the substancewas diflicult to handle, the hydrochloride was prepared by passing dryhydrogen chloride gas through an ether solution of the amine and afterrecrystallization from alcohol-ether mixtures melted at 245-247.

EXAMPLE X(a) A compound having the formula:

EXANIPLE XI A compound having the formula:

may be prepared as follows:

Spiro [cyclohexane 1,1 3 dimethylaminox(1-hydroxybutyl)indanel (0.9 g.)was mixed mo em:

with 'ml. of acetic anhydrideand 1 ml: of" The mixture was heated:slightly" om a: steam cone-to affect solution; and then :allowed' tostand at room temperature for: three days..

dine;

The solvent was then removed-under reduced pressure -to-yield as averyviscous oil, the :acetyl esterof spire [cyclohexane-1,1 3'dimethylamino -x 1 hydroxybutyl) indane].

In the 'same' manner the propionyl' ester was formed using- 'propionic:anhydride and pyridine on' the amino-alcohol,

EXAMPLE 161 A compound having the formula:

may be prepared as-follows Spiro [cyclohexane-Ll-3"-dimethylaminox-(l-hydroxyethyl)indanel (1.1 g.) in ml. of"

anhydrous ether -wasaddedidropwise toth'e Grig nard reagent preparedfrom 127 g; of ethyl iodide and 012 g; of magnesium. After'stirringthereaction at room temperature for an additional hour; 1.1 ml; of aceticanliydride in 20ml. of anhydrous ether'was added dropwise and themi-Xturestirred' for: 22' hours. The mixture was decomposed on" ideand'ammoniaand the ether layerwas washedand dried with anhydrous mag nesiumsulfate. Thedried-"ethersolution wasconcentrated to yield 0.5' g;- oftheoily ester.

Inthe same manner the propionyl" ester was formed using prop-ionioanhydride in place of acetic anhydride;

EXAMPLE; XIII A compound having the formula:

maybe prepared as follows Spiro [cyclohexane-1,1-3-dimethylamino-xethoxyidanel'. To a cooled solution of "5 -ml, of 90% formic acid and '6ml. of 40% formaldehyde was added. 2.1 g. of spiro(cyolohexane-Llf-W-amino-x+ethoxyindane)- hydrochloride and then the mixture was slowlywarmed" on asteam bath. until the evolution of carbon dioxide hadceased." The mixture wasthen concentrated underre-- duced' pressure;made alkaline, and extracted withi ether.. The ether layer was extraotedwithdilute hydrochloric :acid whichliniturn. was neutralized,extractediiwith ether and the. ether extraot'dried overanhydrousimagnesium.sulfate. After re moval cfthe-dryingagent; dryhydrogenxchloride gaswas passedr'intoi thesolution togive'zig; ofcrystalline amine hydrochloride, whichsafterrecrystallization from.acetone melted at 211-213;

XIX/s Aicomppund having the formula:

10: n on EXAMPLE XV A compound having. the formula:

onronhonro r 11 ITI GHa may be prepared as follows:

methylaminoindanel. In the samemanner as above; '7 grof the-amine; 11 g.of anhydrous-aluminumcliloride,- and 3.5 g. of"nbutyryl chloridewas-allowed to reactin carbon disulfide to produceAA g; of spiro[Cyclohexane-LF-x- (n-butyryl)-3-dimethy1aminoindane]; B. P. 15070.4 mm;Ms'Ps 48 49 from'petroleum-ether (2040) The hydrochloride made-in theusual manner was recrystalli'zed from alcohol-ether mixtures andmelted'at 215-218 0;

EXAMPLE; XVI

A. compound havingflthe formula:

if-CH3 CHa may be-hprepared: as follows:

Spiro. [cyclohexanee1,1f xacetyl-3-dimethyl-r aminoindane];v Asolutionof8 g; of aoeticzanhydridea-in'fioiml. of carbon disulfide Was added with.vigorous stirring: to aamixture of 14 g. of:

spiro. [cyolohexane- 1,1" 3 dimethylaminoinclanel', 30 .g; of anhydrousaluminum. chloride and 'ml." of 'oarbon 'disulfiole'. A vigorousreaction 7' 1ensued; which caused.v hydrogen chloride to be evolved;vand whichi caused'the carbon disulfide' toirefluxc: After-the initialreaction had subsided; the mixture was refluxed for an additionaleighteen hours. The cooled mixture was then 7 poured'withstirring intoan ice-sodium hydroxide In the: samemanner as;

solution and the organic layer extracted with ether. The ether layer wasextracted with dilute hydrochloric acid, the aqueous layer madealkaline, extracted with ether, and dried over anhydrous magnesiumsulfate. After removal of the drying agent by filtration, distillationyielded 5 g. of unreacted amine (B. P. 96-106/.08-.09) and 5.7 g. ofspiro [cyclohexane-l,1-x-acetyl-3'-dimethylaminoindanel which boiled at145-160" at 1 mm. The ketoamine was crystallized from petroleum ether(20-40% in a Dry Ice bath and after two sublimations melted at 90-92".

The hydrochloride made in the usual manner was recrystallized frommethanol-ether mixtures and melted at 254-255" (decomp.).

EXAMPLE XVII A compound having the formula:

may be prepared as follows:

Spiro [cyclohexane 1,l-x-nitroindanone-3]. Ten grams of potassiumnitrate in 30 ml. of concentrated sulfuric acid was added dropwise withstirring to a solution of 18.2 g. of spiro[cyclohexane-l,1'-indanone-3l, in 100 ml. of concentrated sulfuric acidcooled to by means of an ice-salt bath. This addition took one and aquarter hours and at no time was the temperature greater than 5. Themixture Was stirred an additional hour at 0 and poured with stirringonto cracked ice. The yellow solid was washed with water, dissolved in500 ml. of hot acetone, clarified and allowed to crystallize slowlyovernight. In this manner, 13.? g. of yellow hexagonal crystals meltingat 193-194" were obtained, concentration of the mother liquors andfinally addition of water produced further fractions which melted at193-194 and gave no mixed melting point depression with the firstfraction. Each fraction was then recrystallized from acetone, benzene,and then acetone, but in each case the melting point was 195-1955 andgave no mixed melting point depression with other fractions. it seemsprobable therefore that nitration of the ketone under these conditionsled to a single positional isomer. The total yield of spiro[cyclohexane-l,1-xnitroindanone-3l was 18 g. or 83%.

Spiro [cyclohexanel,l x aminoindanone- 3']. To a refluxing solution of14.1 g. of the nitroketone in 90 ml. of 95% alcohol was added dropwise,with stirring, 41 g. of stannous chloride dihydrate in 40 ml. ofconcentrated hydrochloric acid and 20 ml. of 95% alcohol. After theaddition, the yellow solution was refluxed an additional thirty minutesand then concentrated under reduced pressure. The residue was madestrongly alkaline with potassium hydroxide so that all of the stannichydroxide remained in solution and the solution extracted with ether.The ether extracts were washed until neutral and then dried overanhydrous magnesium sulfate. After removal of the drying agent andconcentration of the solution, a yellow solid was obtained which, aftercrystallization from benzene-petroleum ether (90-100"), yielded 11 g. or32% of spiro [cyclohexanel,l' x aminoindanone-3'] melting at 116-118".Further re- 16 crystallization from methanol-water mixtures and finallysublimation of and 0.5 mm. produced a nearly white crystalline compoundmelting at -126.

The amino-ketone (10 g.) with 10 g. of hydroxylamine hydrochloride in 55ml. of absolute alcohol and 23 ml. of pyridine was refluxed for threehours. The solution was concentrated to dryness under reduced pressureand the residue dissolved in alcohol, clarified, filtered, and the oximeprecipitated by the slow addition of water. The oxime of spiro[cyclohexane1,lx-aminoindanone-3l (10 g.) so obtained was recrystallizedfrom methanol-water mixtures and melted at 178-180".

Spiro [cyclohexane 1,l'-x-hydroxyindanone 3']. A slurry of 10.5 g. ofthe aminoketone in 11 ml. of concentrated sulfuric acid and 80 ml. ofwater was stirred and cooled to 0 and 3.5 g. of sodium nitrite in 20 ml.of water was added dropwise over a period of forty-five minutes. When apersistent test for nitrous acid was obtained, urea was added to destroythe excess nitrous acid. The solution was filtered and 5 ml. ofconcentrated sulfuric acid in 20 ml. of water was added to the filtrateand the solution heated on a steam bath for one and a quarter hours. Theoily top layer which was formed from this reaction solidified oncooling. The crude brown hydroxyketone was dissolved in ether, the etherlayer extracted with aqueous potassium hydroxide, clarified withcharcoal, filtered and neutralized in the cold with hydrochloric acid toproduce 7.6 g. or 72% of yellow crystalline spiro[cyclohexane-l,lx-hydroxyindanone-3l. Further recrystallization fromalcohol-water mixtures and finally sublimation at 160 and 0.03 mm.yielded a slightly yellow compound melting at 159-160.

Spiro [cyclohexane-l,1 x ethoxyindanone- 3']. lhe hydroxyketone wasethylated with diethyl sulfate according to the directions for thepreparation of vertraldehyde. The product was isolated by etherextraction of the alkaline medium. After drying and removal of thesolvent the residue was distilled at /0.7 mm. Spiro[cyclohexane-1,1-x-ethoxyindanone-3l so obtained, solidified and afterrecrystallization from petroleum ether (30-60") and sublimation at 80and 0.1 mm. melted at 68-70".

The yield of this reaction was low, however, the starting hydroxy ketonecould be recovered by acidification of the original reaction mediumafter the extraction with ether.

The oxime of spiro lcyclohexane-ld x ethoxyindanone-3] prepared in theusual manner, recrystallized from alcohol-water mixtures, and finallysublimed at reduced pressure melted at 151.5-152.

Spiro [cyclohexane l,l-3'-amino-x-ethoxyindane]. The oxime of spiro[cyclohexane-1,l x-ethoxyindanone 3'] (2.? g.) in 50 ml. of glacialacetic acid was hydrogenated at room temperature and 25 pounds ofhydrogen using 1.1 g. of Adams catalyst. After cessation of theabsorption of hydrogen, the catalyst was filtered and the filtrate wascooled and made alkaline. The alkaline solution was extracted withether, dried with anhydrous magnesium sulfate, and concentrated todryness after removal of the drying agent. The remaining brown oil wasconverted into the amine hydrochloride by passing hydrogen chloride gasthrough a dry ether solution of the amine. Recrystallization frommethanol-ether mixtures produced 2.8 g. of spiro-[cyclohexaneit 1.1'aminoe ethoxumdanel hxdroshlcri melting at 234-23.7

EXAMPLE XVIII A compound having the formula:

in 50 ml. of anhydrous benzene was added dropwise to 12 ml. of 1.3 molarlithium aluminum hydride in ether. The mixture was stirred and refluxedfor 18 hours and then decomposed in the cold with water. The organiclayer was dried and concentrated to give 1.3 g. of red oil which formeda dihydrochloride when dry hydrogen chloride gas was passed into a dryether solution of the diamine. This salt was recrystallized from al- Asolution of 1.5. g. of. the...

t actedwith eth r-. dried ethe sp uti n wa concentrated to give 1.2 g.of spiro [cyclohexane 1,1 -x-aminomethyl-;-3 -dimethylaminoidanel In theforegoing examples it will be understood that in lieu of the methylgroup other lower alkyl groups such as ethyl, propyl, etc, may beincorporated in the molecule by proper selection of the reactionmaterials in the manner obvious to those skilled in the art. Likewise,it will be understood that the alkoxy group may be methoxy, ethoxy,propoxy, etc., the acyl group may be acetyl, propionyl, butyryl, etc.,and the halogen may be the chloride, bromide, iodide, fluoride, etc.

The term E313); is used herein as an abbreviation for the minimaleffective dosage for 50% of the animals tested. The term L. D50 is usedherein as an'abbreviation for the lethal dosage for cohol-ether mixturesand melted at 183-188 decomp.)

EXAMPLE XIX A compound having the formula:

HgN-CHr- C/ H/ \N-CH (1H3 may be prepared as follows:

Spiro [cyclohexane 1,1'-x-cyano-3'-dimethylaminoindane] (2.5 g.) in ml.of anhydrous ether was added dropwise to 20 ml. of 1.3 molar lithiumaluminum hydride in anhydrous ether. After the addition, the mixture wasstirred for another hour at room temperature. The mixture was thencooled in an ice bath and decomposed with water. The ether layer wasseparated and concentrated to dryness. The resulting brown oil wastreated with benzoyl chloride and sodium hydroxide to form the solidN-benzoyl derivative. The solid was filtered, washed thoroughly withcold alcohol and then hydrolyzed by boiling with 50 ml. of concentratedhydrochloric acid and 50 ml. of water for ninety-six hours. The cooledacid solution was extracted with ether and the ether layer rejected. Theaqueous acid layer was carefully neutralized and the neutral solutionex- 50% of the animalstested.

It will be understood that other modifications may be made in theforegoing examples without departing from the scope of the invention. Itis intended, therefore, that the patent shall cover by suitableexpression in the appended claims the features of patentable noveltyresiding in the invention.

This application is a continuation-in-part of application Serial No.150,809, filed March 20, 1950, now abandoned.

We claim:

1. A compound represented by the formula R2 in which R1 and R2 areselected from the group consisting of H- and lower alkyl-, and Xrepresents a member of the group consisting of lower alkyl-O, loweralkyl-COO, lower alkyl-CO, hydroxy lower alkyl, and lower fatty acidester of a hydroxy lower alkyl.

2. A compound represented by the formula H: 3. A compound represented bythe formula CHaC 00- o H NCHa a 4. A compound represented by the formula'5. A compound represented by the formula 6. A compound represented bythe formula,

GILBERT FORREST WOODS, JR.

LOUIS H. SCHWARTZMAN.

References Cited in the file of this patent OTHER REFERENCESSchwartzman, Jour. Organic Chem. 15, 517-524 (1950)

1. A COMPOUND REPRESENTED BY THE FORMULA